Retinoid X receptor

{{Short description|Genes on human chromosome 9}}

{{cs1 config|name-list-style=vanc|display-authors=6}}

{{Infobox protein

| Name = retinoid X receptor alpha

| caption =

| image =

| width =

| HGNCid = 10477

| Symbol = RXRA

| AltSymbols =

| EntrezGene = 6256

| OMIM = 180245

| RefSeq = NM_002957

| UniProt = P19793

| PDB =

| ECnumber =

| Chromosome = 9

| Arm = q

| Band = 34

| LocusSupplementaryData =

}}

{{Infobox protein

| Name = retinoid X receptor beta

| caption =

| image =

| width =

| HGNCid = 10478

| Symbol = RXRB

| AltSymbols =

| EntrezGene = 6257

| OMIM = 180246

| RefSeq = NM_021976

| UniProt = P28702

| PDB =

| ECnumber =

| Chromosome = 6

| Arm = p

| Band = 21.3

| LocusSupplementaryData =

}}

{{Infobox protein

| Name = retinoid X receptor gamma

| caption =

| image =

| width =

| HGNCid = 10479

| Symbol = RXRG

| AltSymbols =

| EntrezGene = 6258

| OMIM = 180247

| RefSeq = NM_006917

| UniProt = P48443

| PDB =

| ECnumber =

| Chromosome = 1

| Arm = q

| Band = 22

| LocusSupplementaryData = -q23}}

The retinoid X receptor (RXR){{cite journal | vauthors = Germain P, Chambon P, Eichele G, Evans RM, Lazar MA, Leid M, De Lera AR, Lotan R, Mangelsdorf DJ, Gronemeyer H | title = International Union of Pharmacology. LXIII. Retinoid X receptors | journal = Pharmacological Reviews | volume = 58 | issue = 4 | pages = 760–772 | date = December 2006 | pmid = 17132853 | doi = 10.1124/pr.58.4.7 | s2cid = 1476000 }} is a type of nuclear receptor that is activated by 9-cis retinoic acid, which is discussed controversially to be of endogenous relevance,{{cite journal | vauthors = de Lera ÁR, Krezel W, Rühl R | title = An Endogenous Mammalian Retinoid X Receptor Ligand, At Last! | journal = ChemMedChem | volume = 11 | issue = 10 | pages = 1027–1037 | date = May 2016 | pmid = 27151148 | doi = 10.1002/cmdc.201600105 | s2cid = 269196 }}{{cite journal | vauthors = Allenby G, Bocquel MT, Saunders M, Kazmer S, Speck J, Rosenberger M, Lovey A, Kastner P, Grippo JF, Chambon P | title = Retinoic acid receptors and retinoid X receptors: interactions with endogenous retinoic acids | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 90 | issue = 1 | pages = 30–34 | date = January 1993 | pmid = 8380496 | pmc = 45593 | doi = 10.1073/pnas.90.1.30 | doi-access = free | bibcode = 1993PNAS...90...30A }} and 9-cis-13,14-dihydroretinoic acid, which may be an endogenous mammalian RXR-selective agonist.{{cite journal | vauthors = Rühl R, Krzyżosiak A, Niewiadomska-Cimicka A, Rochel N, Szeles L, Vaz B, Wietrzych-Schindler M, Álvarez S, Szklenar M, Nagy L, de Lera AR, Krężel W | title = 9-cis-13,14-Dihydroretinoic Acid Is an Endogenous Retinoid Acting as RXR Ligand in Mice | journal = PLOS Genetics | volume = 11 | issue = 6 | pages = e1005213 | date = June 2015 | pmid = 26030625 | pmc = 4451509 | doi = 10.1371/journal.pgen.1005213 | doi-access = free }} Bexarotene is the only specific activator of the RXRs which does not activate the Retinoic Acid Receptors.{{cite journal | vauthors = Panchal MR, Scarisbrick JJ | title = The utility of bexarotene in mycosis fungoides and Sézary syndrome | journal = OncoTargets and Therapy | volume = 8 | pages = 367–373 | date = 2015-02-03 | pmid = 25678803 | pmc = 4322887 | doi = 10.2147/OTT.S61308 | doi-access = free }}

There are three retinoic X receptors (RXR): RXR-alpha, RXR-beta, and RXR-gamma, encoded by the {{gene|RXRA}}, {{gene|RXRB}}, {{gene|RXRG}} genes, respectively.

RXR heterodimerizes with multiple nuclear receptors including CAR, FXR, LXR, PPAR,{{cite journal | vauthors = Plutzky J | title = The PPAR-RXR transcriptional complex in the vasculature: energy in the balance | journal = Circulation Research | volume = 108 | issue = 8 | pages = 1002–1016 | date = April 2011 | pmid = 21493923 | doi = 10.1161/CIRCRESAHA.110.226860 | doi-access = free }} PXR, RAR, TR, ER and VDR. RXRs are permissive co-receptors as only one of six alleles is needed for normal development and health.{{cite journal | vauthors = Krezel W, Dupé V, Mark M, Dierich A, Kastner P, Chambon P | title = RXR gamma null mice are apparently normal and compound RXR alpha +/-/RXR beta -/-/RXR gamma -/- mutant mice are viable | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 93 | issue = 17 | pages = 9010–9014 | date = August 1996 | pmid = 8799145 | pmc = 38586 | doi = 10.1073/pnas.93.17.9010 | doi-access = free }} Given this, it is difficult to extrapolate whether the RXR pathway has its own endogenous activity driven by 9-cis retinoic acid species or whether it merely participates in other pathways, predominantly the retinoic nuclear receptor pathway. Genomic knockout of the RXRs results in obesity resistance{{cite journal | vauthors = Haugen BR, Jensen DR, Sharma V, Pulawa LK, Hays WR, Krezel W, Chambon P, Eckel RH | title = Retinoid X receptor gamma-deficient mice have increased skeletal muscle lipoprotein lipase activity and less weight gain when fed a high-fat diet | journal = Endocrinology | volume = 145 | issue = 8 | pages = 3679–3685 | date = August 2004 | pmid = 15087432 | doi = 10.1210/en.2003-1401 }} while bexarotene treatment causes severe hypothyroidism,{{cite journal | vauthors = Esposito M, Amory JK, Kang Y | title = The pathogenic role of retinoid nuclear receptor signaling in cancer and metabolic syndromes | journal = The Journal of Experimental Medicine | volume = 221 | issue = 9 | date = September 2024 | pmid = 39133222 | doi = 10.1084/jem.20240519 | doi-access = free | pmc = 11318670 }} suggesting that the RXR pathway functions at least to regulate the Thyroid Receptor pathway.

As with other type II nuclear receptors, the RXR heterodimer in the absence of ligand is bound to hormone response elements complexed with corepressor protein. Binding of agonist ligands to RXR results in dissociation of corepressor and recruitment of coactivator protein, which, in turn, promotes transcription of the downstream target gene into mRNA and eventually protein.